1. Field of the Invention
The present invention provides new methods for preparation of 2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran (xe2x80x9ccompound 1xe2x80x9d) and synthetic precursors thereof.
2. Background
Leukotrienes are recognized potent local mediators, playing a significant role in inflammatory and allegeric responses, including arthritis, asthma, psoriasis and thrombotic disease. Leukotrienes are produced by the oxidation of arachidonic acid by lipoxygenase. More particularly, arachidonic acid is oxidized by 5-lipooxygenase to the hydroperoxide 5-hydroperoxy-eicosatetraenoic acid (5-HPETE), that is converted to leukotriene A4, that in turn can be converted to leukotriene B4, C4, or D4. The slow-reacting substance of anaphylaxis is now known to be a mixture of leukotrienes C4, D4 and E4, all of which are potent bronchoconstrictors.
Efforts have been made to identify receptor antagonists or inhibitors of leukotriene biosynthesis, to prevent or minimize pathogenic inflammatory responses mediated by leukotrienes.
For example, European Patent Application Nos. 901171171.0 and 901170171.0 report indole, benzofuran, and benzothiophene lipoxygenase inhibiting compounds.
Various 2,5-disubstituted tetrahydrofurans have exhibited significant biological activity, including as lipoxygenase inhibitors. See U.S. Pat. Nos. 5,703,093; 5,681,966; 5,648,486; 5,434,151; and 5,358,938.
While such compounds are highly useful therapeutic agents, current methods for synthesis of least some of the compounds require lengthy routes, and reagents and protocols that are less preferred in larger scale operations, such as to produce kilogram quantities.
We have now found new methods for preparation of 2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofaran and precursor compounds thereof. 2-(4-Fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran is sometimes referred to herein as xe2x80x9ccompound 1xe2x80x9d. Preferred methods of the invention provide compound 1 in optically active form, particularly as an enantiomerically enriched mixture of the following stereoisomer (i.e. 2S,5S-trans-2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran): 
The methods of the invention utilize reagents and synthetic protocols that facilitate large scale manufacture, and provide increased yields relative to prior approaches.
In a first aspect of the invention, compound 1 and precursors thereof are provided by reacting 4-fluorophenol with an epoxide having a reactive C3 carbon, e.g. a glycidyl compound substituted at the C3 position with an electron-withdrawing group such as halo (e.g. epichlorohydrin, epibromohydrin), mesyl or tosyl (glycidyl mesylate and glycidyl tosylate), etc., to form an epoxyphenylether ((glycidyl-4-fluorophenyl ether) in the presence of base and preferably at or above about 0xc2x0 C. The reacted epoxide can be optically active if desired. The formed epoxyphenylether is then reacted with an active methylene compound to form a lactone, preferably a xcex3-lactone, with 5 ring members. The active methylene compound can be a variety of agents. Diethyl and dimethyl malonate are generally preferred, which provide an ethyl or methyl ester as a lactone ring substituent, i.e. 2-carboalkoxy-(4-fluoro-phenoxy-methyl)-xcex3-butyrolactone, where the alkoxy group suitably has from 1 to about 12 carbon atoms, more preferably 1 to about 6 carbon atoms, still more preferably 1 to about 3 carbons with methoxy and ethoxy particularly preferred. That ester group is then removed (e.g. via hydrolysis and decarboxylation), and the lactone suitably reduced to a hydroxy-substituted tetrahydrofuran, specifically 4-fluorophenoxymethyl-hydroxytetrahydrofuran.
The hydroxy tetrahydrofuran is further functionalized by activating the hydroxyl substituent of the hydroxytetrahydrofuran-phenyl ether followed by substitution of the corresponding position of the tetrahydrofuran ring with by a 1-alkyne reagent. Also, rather than directly activating the hydroxyl moiety, that group can be replaced with a halide, and the halide-substituted tetrahydrofuran reacted with a benzylsulfonic acid reagent.
It also has been found that methods of the invention enable such substitution of the tetrahydrofuran to proceed with extremely high stereoselectivity, e.g. at least greater than about 60 mole percent of one stereoisomer than the other, more typically greater than about 70 or 75 mole percent of one stereoisomer than the other isomer. Recrystallization has provided very high optical purities, e.g. about 95 mole %, 97 mole % or even 99 mole % or more of the single stereoisomer.
In another aspect, methods are provided that involve cleavage of a bis-compound to provide high yields of compound 1. These methods preferably involve condensation of mannitol with an alkanoyl particularly an aldehyde such as formaldehyde to form a trialkylene mannitol such as a tri(C1-10alkylene) mannitol e.g. trimethylene mannitol when using formaldehyde, which is then cleaved to form 2,5,-O-methylene-mannitol, which has two primary hydroxyl groups and two secondary hydroxyl groups. The primary hydroxyl groups are protected (e.g. as esters) and the secondary hydroxyl groups then are suitably cyclized, e.g. with a trialkylorthoformate reagent, to provide a cyclic ether. The protected primary alcohols are then converted to aryl ethers, followed by cleavage of the cyclic ether to provide again the secondary hydroxyl groups. The mannitol compound then undergoes oxidative cleavage to provide the corresponding alicyclic dialdehyde, which aldehyde groups are functionalized to bis-xcex1,xcex2-unsaturated esters. The carbon-carbon double bonds of that compound are suitably saturated, and the bis-compound cleaved and the cleavage products cyclized to provide two molar equivalents of 4-fluorophenoxy-methyl-xcex3-butyrolactone which can be further functionalized as described above.
In yet another aspect of the invention, preparative methods are provided that include multiple reactions that surprisingly proceed as a single step without isolation of intermediates to provide compound 1.
Moreover, it has been surprisingly found that the one step procedure is enantioselective. Hence, if the starting reagent (a 2,3-epoxide) is optically active, the resulting compound 1 also will be optically active.
More particularly, in this aspect of the invention, a compound is reacted that has at least a six-carbon alkyl or alkylene chain that is activated at the 1- and 6-carbon positions such as by substitution by suitable leaving groups, and 2- and 3-carbon positions of the chain form an epoxide ring. The compound suitably has about 6-12 carbons in the chain. The leaving groups of the 1- and 6-positions may be e.g. halo, such as chloro or bromo, or an ester, such as an alkyl or aryl sulfonic ester, e.g. mesylate or other C1-10 alkyl sulfonic ester, or a phenyl sulfonic ester such as tosylate and the like, or an arylalkyl ester such as benzylsulfonic ester. Preferably, the 1-position is halo-substituted, particularly bromo-, iodo- or chloro-substituted, and the 6-position is substituted by an ester such as by a benzylsulfonyl group. That compound is reacted with a molar excess of a strong base such as an alkyllithium reagent that affords compound 1 in a single step.
In another aspect of the invention, a chiral synthon is preferably employed such as glyceraldehyde, mannitol, ascorbic acid, and the like, to provide a stereoselective route to desired stereoisomers of compound 1. This route includes formation of a substituted dioxolane, typically a 1,3-dioxolane (particularly (2,2-dimethyl)- 1,3-dioxolane), which preferably is optically active. A side chain of the dioxolane, preferably at the 4-position, is suitably extended e.g. by one or more Wittig reactions, typically one or two Wittig reactions that provide B-unsaturated moieties such as an xcex1,xcex2-unsaturated alkyl ester. Such an xcex1,xcex2-unsaturated moiety provided then can be epoxidized, preferably by asymmetric oxidation of the conjugated alkene to provide an optically active epoxide, which then participates in an elimination reaction to yield a propargyl alcohol as the dioxolane ring substituent. The dioxolane ring then can be opened, typically in the presence of acid and the acyclic intermediate cyclized to provide an optically active tetrahydrofuran that is 1-alkyne-4-hydroxyalkyl-substituted, preferably 1-ethynyl4-hydroxymethyl-substituted. See generally Schemes VIII through X and the discussion related thereto below. The substituted tetrahydrofuran can be further functionalized as outlined above to provide compound 1. For instance, the primary hydroxy of the alkylhydroxy substituent can be esterified (e.g., sulfonate such as a tosylate) and the activated carbon reacted to provide an aryl substituent, particularly para-fluorophenyl. The alkynyl substituent can be extended to provided the hydroxy urea as discussed above.
In an alternative method of the invention, a substituted dioxolane reagent is employed, again typically a 1,3-dioxolane (particularly (2,2-dimethyl)- 1,3-dioxolane), which preferably is optically active. The dioxolane has an alkanoyl side chain, more particularly a propionaldehyde (xe2x80x94CH2CH2C(xe2x95x90O)H) substituent that is reacted suitably in the presence of base (e.g. an alkyllithium) with a 1-alkyne to provide a proparyl alcohol. The alkyne reagent is preferably a butynyl compound with terminal ether group, preferably a terminal aryl or alkaryl ether such as optionally substituted 1-(4-phenylmethylether)-butynyl. The resulting substituted dioxolane can be opened suitably in the presence of acid to an acyclic intermediate, followed by cyclization under basic conditions to provide a substituted tetrahydrofuran which can be further functionalized as discussed above with respect to Schemes VIII through X to provide compound 1. See generally Scheme XI and the discussion related thereto below.
In a further synthetic route of the invention, a substituted dioxolane reagent is employed, again typically a 1,3-dioxolane (particularly (2,2-dimethyl)- 1,3-dioxolane), which preferably is optically active. The dioloxane has a keto alkyne side chain, preferably xe2x80x94CH2CH2C(xe2x95x90O)Cxe2x89xa1CR where R is optionally substituted alkyl, particularly C1-6 alkyl, or an alkylether or alkaryl ether such as a C1-6 ether, preferably an ethyl aryl or other (C)alkylaryl ether such as xe2x80x94CH2CH2OCH2(phenyl or substituted phenyl). The keto group is then reduced, preferably asymmetrically such as by use of a chiral catalyst, to provide a propargyl alcohol that can be further functionalized to compound 1 as generally discussed above. See Scheme XII and the related discussion below.
In yet a further aspect of the invention, an alkyne-substituted tetrahydrofuran is prepared directly (e.g., without a dioxolane intermediate) from an acyclic keto alkyne compound. More specifically, a keto alkynyl reagent with terminal alkenyl group is suitably employed, e.g. xe2x80x94CH2xe2x95x90CHCH2CH2C(xe2x95x90O)Cxe2x89xa1CR where R is the same as defined immediately above. The terminal alkene is then epoxidized, e.g. by ozonolysis or other suitable oxidant. The epoxidized keto alkyne then can be reduced and internally cyclized, e.g. in the presence of a suitable reducing agent such as diborone methyl sulfide, and then functionalized to compound 1 as generally discussed above.
As mentioned above, compound 1will be useful for therapeutic applications, and may be employed to treat disorders or diseases mediated by 5-lipoxygenase such as immune, allegeric and cardiovascular disorders and diseases, e.g. general inflammation, hypertension, skeletal-muscular disorders, osteoarthritis, gout, asthma, lung edema, adult respiratory distress syndrome, pain, aggregation of platelets, shock, rheumatoid arthritis, psoriatic arthritis, psoriasis, autoimmune uveitis, allergic encephalomyelitis, systemic lupus erythematosis, acute necrotizing hemmorrhagic encephalopathy, idiopathic thrombocytopenia, polychondritis, chronic active hepatitis, idiopathic sprue, Crohn""s disease, Graves ophthalmopathy, primary biliary cirrhosis, uveitis posterior, interstitial lung fibrosis, allergic asthma and inappropriate allergic responses to environmental stimuli.
Compound 1 produced by the methods of the invention will be useful as a synthetic intermediate to prepare other compounds that will be useful for therapeutic applications. Other aspects of the invention are disclosed infra.
Particularly preferred preparative methods of the invention are exemplified in the following Schemes I through XIV. For purposes of exemplification only, particularly preferred compounds are depicted in the Schemes, and it will be understood that a variety of other compounds can be employed in similar manner as described below with respect to the exemplified compounds. 
Scheme I exemplifies a preferred preparative method of the invention wherein arylhydroxide 2 is reacted with epoxide 3 having a reactive C3 carbon. Preferred epoxides are those that are enantiomerically enriched, such as the glycidyl tosylate 3 shown above that is condensed with phenol 2 for a time and temperature sufficient for reaction completion to provide epoxyaryl ether 4. See Example 1, Part 1 below for exemplary reaction conditions. The reagents 2 and 3 are typically reacted in a suitable solvent, e.g. dimethyl formamide, N-methyl pyrrolidinone and the like. Enantiomerically enriched epoxides suitable for condensation with an arylhydroxide are commercially available or can be readily prepared by known procedures. See, for instance, U.S. Pat. Nos. 4,946,974 and 5,332,843 to Sharpless et al. for preparation of optically active derivatives of glycidol.
The epoxyaryl ether 4 then is reacted with an active methylene group, such a diethyl or dimethyl malonate to provide butyrolactone 5. The exocyclic ester of 5 is then suitably cleaved, e.g. with reaction with magnesium chloride hexahydrate, to provide the aryllactone ether 6. See Example 1, Part 3 which follows for an exemplary reaction conditions. That lactone 6 is then reduced to the hydroxy-tetrahydrofuran 7. Suitable reducing agents include e.g. DIBAL-H and the like. See Example 1, Part 4, which follows. 
Schemes II and III exemplify further preferred methods of the invention for synthesis of compound 1 and precursors thereof. More specifically, the hydroxy substituent of tetrahydrofuran 7 is preferably protected, e.g. as an ether or ester. Thus, as depicted in Schemes II and III, the hydroxy moiety of 7 can be reacted with a suitable silyl reagent, e.g. to form the t-butyldimethylsilyl ether 8, or with reagent for esterification, e.g. an anhydride such as acetic anhydride to acetyl ester 11. See Example 1, Part 5 and Example 2, Part 1 for suitable reaction conditions for exemplary conditions.
The protected phenyltetrahydrofuran ether 8 or 11 then can reacted to provide the alkynyl-substituted tetrahydrofuran 9 by treatment with a 1-alkyne in the presence of a strong base such an alkyllithium. Preferably the alkyne reagent contains a protected hydroxy moiety such as a silyl ether, e.g. a tetrahydropyranyl ether as depicted in the above Schemes. The hydroxy group can be readily deprotected after coupling of the alkynyl reagent to the tetrahydrofuran ring, e.g. by treatment with dilute acid. Typically, the alkyne reagent will contain a primary or secondary hydroxy moiety. 
Schemes IV and V above exemplify further convenient routes that can provide compound 1 and precursors thereof. Thus, in Scheme IV, halo-substituted compound 12 can be reacted with an alkyne reagent as generally described above with respect to Schemes II and III to provide 9, which can be readily deprotected to provide the primary alcohol of compound 10. See generally Example 3 which follows for exemplary reaction conditions.
In Scheme V, hydroxytetrahydrofuran 7 is condensed with a sulfinic acid reagent to provide the phenylsulfinic acid ester 8 which can be reacted with an alkyne reagent as generally described above to provide 9. Compound 10 is readily provided by treatment of the protected alcohol 9 with treatment with dilute acid. See Example 4 below.
It also has been found that enhanced yields can be obtained by use of a phenylsulfinic acid reagent that is substituted at one or more positions on the phenyl ring, rather than the unsubstituted phenylsulfinic reagent. Methylphenylsulfinic acid, including p-methylphenylsulfinic acid is particularly preferred, although phenyl ring substituents will be suitable in addition to methyl, including both electron-withdrawing and electron-donating phenyl ring substituents such as one or more C1-12alkyl groups more typically one or more C1-8alkyl or C1-6alkyl groups, C1-12 alkoxy or more typically C1-6alkoxy, cyano, nitro and the like. Para substitution of the phenyl reagent is generally preferred, although other phenyl ring positions also may be suitably substituted.
Scheme VI below exemplifies a further preferred method of the invention that can provide compound 1 and precursors thereof in high yields and involves cleavage of a bis-compound. 
More specifically, as depicted above, trimethylene mannitol 16 is suitably prepared by condensation of mannitol 15 with formaldehyde in the presence of acid. The labile rings are cleaved and the resulting esters of 17 reduced to the primary and secondary alcohols of 18. The primary alcohols are protected, e.g. as an allyl or aryl sulfonic ester, to provide intermediate 19. The secondary hydroxyl groups of 19 then are functionalized by reaction with a trialkylorthoformate, e.g. a tri(C1-10alkyl)orthoformate such as triethylorthoformate, to provide 20. The protected primary alcohols of 20 are then converted to 4-fluorophenyl ethers, preferably under basic conditions by reaction with 4-fluorophenol to provide di-(4-fluorophenyl)ether 21. That phenyl ether is then reacted in the presence of acid to cleave the methylene ethers to provide secondary hydroxyl groups of compound 22.
Compound 22 then undergoes oxidative cleavage by treatment with a suitable reagent such as Pb(OAc)4, and the resulting dialdehyde is functionalized to the acyclic bis-(xcex1,xcex2-unsaturated) compound, preferably bis-xcex1,xcex2-unsaturated ester 23 such as by reaction with carboethoxymethylenetriphenyl phosphorane. Other xcex1,xcex2-unsaturated groups will be suitable for the alicyclic compound, e.g. xcex1,xcex2-unsaturated esters having 1 to about 12 carbon atoms, xcex1,xcex2-unsaturated acids, and other Michael-type acceptors. The carbon-carbon double bonds of 23 then are saturated, preferably by hydrogenation, and the resulting compound is cleaved and cyclized in the presence of acid to form the aryl ether 6. In one system, the saturated compound is refluxed in a suitable solvent such as an alcohol, ethanol, for a time sufficient to provide 6.  See Example 5 which follows for exemplary reagents and reaction conditions. Compound 6 then can be further functionalized, e.g. as discussed above with respect to Schemes II and III. 
Scheme VII above exemplifies a further preferred method of the invention that provides compound 1 and precursors thereof and features multiple reactions that proceed as a single step without isolation of intermediates.
More specifically, as shown above compound 2 is reacted with epoxide 24 that has a reactive C3 carbon to provide the fluorophenylepoxy ether 25. If the epoxide 24 is not enantiomerically enriched such as 3, the fluorophenylepoxy ether 25 may be resolved if desired such as by procedures generally depicted in Scheme VI above to provide optically active epoxide ethers 27 and 4. See Example 6, Parts 2-4 below for exemplary reagents and reaction conditions. That procedure generally entails formation of optically active fluorophenyldiol ether and fluorophenylepoxide ether 26 and 27 from the racemic fluorophenylepoxide 25 with an optically active reagent, preferably an optically active catalyst such as Jacobsen""s catalyst. See E. Jacobsen, Science, 277:936-938 (1997). The optically active diol 26 can be readily cyclized to the epoxide 4, for example by esterification (e.g. a sulfonic ester as shown exemplified by 28 above) of the primary hydroxyl group of the diol followed by epoxide formation under basic conditions (e.g. NaH).
An allyl halide is suitably reacted with the phenylepoxide ether, suitably in the presence of Mg, catalytic amount of iodine and cuprous cyanide to provide arylalkene ether 29. The secondary hydroxy is suitably protected, e.g. as an ester, preferably as a sulfonic ester, to provide 30. An ester group is then suitably grafted to terminal carbon-carbon double bond to the xcex1,xcex2-unsaturated ester 31, and the ester reduced to the alcohol, typically by treatment with strong base such as DIBAL-H.
The alkene is then suitably oxidized to provide epoxy group of 33. The oxidation may be conducted to provide optically active epoxy carbons as generally shown in Scheme VI (compound 33) and conducted using suitable optically active reagent(s) such as an optically active catalyst or other reagent. See Example 6, Part 9 for an exemplary procedure. The racemic epoxides also may be resolved, e.g. by chromatography using an optically active packing material. The glycidyl compound 33 is then converted to the epihalohydrin 34.
The epihalohydrin 34, in a single step, is converted to the alkynyltetrahydrofuran ether 35 upon treatment with a molar excess, preferably at least about a three molar excess of a strong base such as an alkyllithium reagent or sodium amide. BuLi is generally preferred, particularly n-BuLi.
While not being bound by theory, it is believed the single step reaction proceeds through the mechanism shown immediately below, where Ar is 4-fluorophenyl and Ms is mesyl (xe2x80x94S(O)2CH3): 
The alkynyl group of compound 35 can be further functionalized as desired, e.g. by reaction with ethylene oxide in the presence of base to afford the single enantiomer 10. Compound 10 is further functionalized to produce compound 1 suitably by reacting compound 10 with N,O-bisphenoxycarbonyl hydroxylamine and triphenylphosphine and diisopropylazo-dicarboxylate, followed by treatment of resulting intermediate with NH3.
More preferably, compound 1 is generated from 10 via a protected hydroxyurea (e.g., a compound of the formula NH2C(O)NHOR, where R is a hydroxy protecting group such as para-methoxybenzyl-) is reacted with a substituted alcohol compound such as 10 of Scheme II, preferably in the presence of suitable dehydrating agent(s) such as triphenyl phosphine and diethylazodicarboxylate (DEAD), to provide an amino ester, i.e. a moiety of the formula xe2x80x94NRC(O)OR1R where R is as defined immediately above and R1 is a non-hydrogen group such as aryl, particularly phenyl, alkyl, e.g. C1-10 alkyl, etc. That amino ester is then treated with ammonia and a Lewis acid such as boron trifluoride etherate and the like to provide compound 1.
Scheme VIII shows another preferred preparative method of the invention that employs a polyol reagent. As depicted in the below Scheme, the entire reaction is stereoselective (i.e. no separate resolution step or procedure required), beginning with the optically active mannitol 1, which is commercially available. Other glyceraldehyde steroisomers can be employed in the same manner as depicted in Scheme VIII to provide the corresponding distinct stereoisomer as the reaction scheme product.
In the following Schemes VIII through XIV, the compound numerals in the discussions of those Schemes are made in reference to the compound depicted in the particular Scheme, with the exception of compound 1, i.e. 2-(4-fluorophenoxymethyl)-5-(4N-hydroxyureidyl-1-butynyl)-tetrahydrofuran.
As generally exemplified in Scheme VIII below, the chiral synthon (mannitol) is cyclized in the presence of base to the bis-dioxolane compound 2 which is then oxidized to the keto dioxolane 3 and reacted with an appropriate Wittig reagent to provide the xcex1,xcex2-unsaturated ester 4. As referred to herein, unless specified otherwise, the term xe2x80x9cWittig reactionxe2x80x9d or xe2x80x9cWittig-type reactionxe2x80x9d designates any of the broad classes of alkene-formation reactions, typically involving ylide intermediates such as may be provided by phosphonate and phosphorane reagents. Additionally, as referred to herein, unless otherwise specified, to xe2x80x9cketoxe2x80x9d, xe2x80x9ccarbonylxe2x80x9d, or xe2x80x9ccarboxyxe2x80x9d or like term designate any functional group that includes a carbon-oxygen double bond (Cxe2x95x90O).
The carbon-carbon double bond produced by the Wittig reaction then can be saturated, e.g. hydrogenated in the presence of a suitable catalyst such as PtO2, and the ester reduced and then oxidized to provide aldehyde 7. Wittig reaction of the aldehyde moiety provides the xcex1,xcex2-unsaturated compound 9 which can be reduced to alcohol 9, and converted to the propargyl compound, e.g. via an epoxidized intermediate. More specifically, unsaturated alcohol 9 can be epoxidized to compound 10 suitably with an optically active oxidant and then elimination of the epihalohydrin derivative 11 in the presence of a suitable base e.g. LDA or other suitable agent to provide the propargyl compound 12. Acidic opening of the dioxolane ring provides diol 14 and esterification (e.g., sulfonate ester such as a tosylate) provides the substituted tetrahydrofuran 16. The resulting hydroxy tetrahydrofuran can be functionalized as desired, e.g. esterification of the hydroxy followed by aryl substitution and functionalization of the alkynyl group provides compound 1, particularly 2S,5S-trans-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran. See, generally, Example 7 which follows for exemplary preferred reaction procedures. 
Scheme IX depicts a related approach to provide another stereoisomer of the substituted alkyne terahydrofuran compound. As shown in Scheme IX, L-ascorbic acid can be employed as a starting reagent to provide hydroxy dioxolane compound 19 which is oxidized; subjected to multiple Witting reactions; epoxidized; and an epihalohydrin intermediate reacted in the presence of base to form a propargyl alcohol intermediate, which is converted to the optically active aryl-substituted alkyne tetrahydrofuran compounds 33 and 34. See Example 8 which follows, for exemplary preferred reaction conditions. The resulting tetrahydrofuran can be modified to compound 1, specifically functionalization of the alkynyl group as discussed above, particularly 2R,5R-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran. 
It should be appreciated that the unsubstituted alkyne produced through the routes of Schemes VIII and IX above is a versatile intermediate that can be further reacted to provide a wide range of moieties, including groups that can be detected, either upon in vitro or in vivo applications. For instance, the unsubstituted alkyne can be reacted with a group to provide radiolabeled and stable isotopic moieties e.g. 125I, 3H, 32P, 99Tc, 14C, 13C, 15N or the like, which may be useful inter alia for mechanistic studies.
Scheme X below depicts another route related to Schemes VIII and LX above and employs multiple Wittig reactions to provide a further stereoisomer of compound L, specifically 2R,5S-2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran. See Example 9 which follows for exemplary reaction conditions. 
Scheme XI below exemplifies further methods of the invention that utilize dioxolane intermediate 7. Rather than employing multiple Wittig reactions, a 1-alkyne is reacted with aldehyde reagent 7, the resulting dioxolane 35 esterified and the dioxolane ring opened in the presence of acid, followed by cyclization in the presence of base, suitable a relatively weak base such as K2CO3. The cyclization of 38 to optically active substituted tetrahydrofuran 39 can proceed with high stereoselectivity. The resulting tetrahydrofuran then can be further functionalized to provide 2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran. See Example 10 which follows, for exemplary preferred reaction conditions. 
Scheme XII below depicts another convenient route to compound 1 that entails a single Wittig reaction. More particularly, the dioxolane aldehyde reagent is reacted with a Wittig reagent, the resulting alkene saturated such as by hydrogenation and the alkyl ester converted to acid 57. The acid is then reacted with a chloroformate reagent in the presence of base, and the resulting intermediate reacted with 1-(4-methoxy phenylmethylether)-butynyl in the presence of a strong base, such as an alkyl lithium e.g. butyllithium. The keto alkyne dioxolane compound 58 is then reduced asymmetrically in the presence of a suitable chiral catalyst, e.g. an optically active pinene and BBN. The resulting optically active propargyl alcohol can be reacted as outlined above to provide compound 1, particularly 2S,5S-trans-2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran. See Example II which follows for exemplary reaction conditions. 
Scheme XIII below depicts a highly efficient route to 2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran. As shown in the Scheme, butynyl reagent 52 is treated with base, preferably a strong base such as an alkyl lithium e.g. butyl lithium, and then reacted with an unsaturated anhydride 53 to provide the keto alkynyl compound 54 with terminal alkene group. The alkene group is oxidized, e.g. via ozonolysis, and the keto-epoxide compound 55 reduced and cyclized typically in the presence of a suitable reducing agent, e.g. diborane methyl sulfide. The resulting hydroxy tetrahydrofuran can be functionalized as desired, e.g. esterification of the hydroxy moiety followed by aryl substitution and functionalization of the alkynyl Croup provides 2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran. See Example 12 which follows for exemplary preferred reaction conditions. 
In another aspect of the invention, it has been found that that a lactone, particularly butyrolactone such as xcex3-butyrolactone ring-substituted (suitably at an xcex1 position) by an activated ester (e.g., sulfonate ester such as tosylate, mesylate, etc.) can be reacted with an aryl nucleophile to provide in good yields a methylene aryloxy group. More specifically, with reference to Scheme XIV below, compound 60 will undergo a displacement reaction with an aryl nucleophile in the presence of a hydride reagent (base), such as potassium hydride or more preferably sodium hydride to yield the tetrahydrofuran arylether 61. Preferred aryl nucleophiles include aryl compounds having one or more hydroxy ring substituents (i.e. an aryl hydroxy compound), particularly carbocyclic aryl compounds such as phenol, particularly 4-fluorophenol. See Example 13 which follows for exemplary preferred reaction conditions. It has been found that this substitution reaction proceeds without opening or other undesired attack of the lactone ring. In Scheme XIV, the substituent R is compound 60 is suitably hydrogen, alkyl e.g. C1-8 alkyl and the like; and the substituent Rxe2x80x2 is suitably aryl as specified herein, particularly phenyl, more preferably 4-fluorophenyl. Compound 60 can be readily functionalized to provide compound 1, particularly by the procedures discussed above with respect to Schemes I and II. 
As discussed above, compound 1 will be useful for numerous therapeutic applications. The compounds can be administered to a subject, particularly a mammal such as a human, in need of treatment, by a variety of routes. For example, the compound can be administered orally, parenterally, intravenously, intradermally, subcutaneously, or topically.
The active compound may be administered to a subject as a pharmaceutically active salt, e.g. salts formed by addition of an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc., or an organic acid such as acetic acid, oxalic acid, tartaric acid, succinic acid, etc. Base addition salts also can be formulated if an appropriate acidic group is present on the compound. For example, suitable base addition salts include those formed by addition of metal cations such as zinc, calcium, etc., or salts formed by addition of ammonium, tetraethylammonium, etc. Suitable dosages for a given therapy can be readily determined by the medical practitioner such as by standard dosing protocols. See also U.S. Pat. No. 5,703,093.
Often, it will be preferable to use an optically active or enantiometrically enriched mixture of compound 1 for a given therapeutic application. As used herein, the term xe2x80x9cenantiometrically enrichedxe2x80x9d typically refers to a compound mixture that is at least approximately 70 mole %, 80 mole %, 85 mole % or 90 mole % of a single stereoisomer, and preferably a compound mixture that contains approximately at least about 92 mole %, 95 mole %, 97 mole %, 98 mole %, 99 mole % or 100% of a single enantiomer of the compound.
As used herein, the term halo, halogen or the like refers to fluoro, chloro, bromo or iodo. The term alkyl typically refers an alkyl group having 1 to about 20 carbon atoms, more typically 1 to about 12 carbon atoms, still more typically 1 to about 6 or 8 carbon atoms. The term arylalkyl refers to a carbocyclic aryl such as phenyl that is substituted on an alkyl, particularly alkyl having 1 to about 6 to 8 carbons.
All documents mentioned herein are incorporated herein by reference.
The following non-limiting examples are illustrative of the invention.